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Tetrahydronaphthyridine derivatives and a process for preparing the same

a technology of tetrahydronaphthyridine and tetrahydronaphthyridine, which is applied in the direction of drug composition, extracellular fluid disorder, metabolic disorder, etc., can solve the problems of insufficient drug use, limited preventive effect of coronary diseases, and insufficient drug use, so as to improve hdl cholesterol, prevent and/or treat the disease, and reduce the ldl cholesterol.

Inactive Publication Date: 2007-02-08
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides novel tetrahydronaphthyridine derivatives having an excellent CETP inhibitory activity wherein defects of existing CETP inhibitory compounds are rectified.

Problems solved by technology

However, their preventive effect on coronary diseases is limited to some extent, and is not satisfactory enough yet.
However, there are no drugs that can be used in a satisfactory manner for this purpose.
Fibrates and HMG-CoA reductase inhibitors have only low activity of increasing HDL cholesterol; nicotinic acid derivatives can significantly increase HDL, but have serious toleration issues.
However, these compounds have defects.
That is, they are poorly soluble in water and cannot be absorbed enough in vivo, a sufficient blood level for taking medicinal effect can hardly be achieved even when administered as an ordinary formulation for oral administration.

Method used

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  • Tetrahydronaphthyridine derivatives and a process for preparing the same
  • Tetrahydronaphthyridine derivatives and a process for preparing the same
  • Tetrahydronaphthyridine derivatives and a process for preparing the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

(1) A solution of 5-amino-2-methoxypyridine (10 g) in toluene (20 ml) is added dropwise to a suspension of benzotriazole (9.6 g) in toluene (150 ml). Then, a solution of propionaldehyde (6.35 ml) in toluene (20 ml) is added thereto dropwise at 30° C. or below, and the mixture is stirred at room temperature overnight. The suspension is filtered and the resulting crystals are washed with ether to give (1-benzotriazol-1-yl-propyl)-(6-methoxypyridin-3-yl)amine (19.7 g). mp.:109.3-110.3° C.

(2) (1-Benzotriazol-1-yl-propyl)-(6-methoxypyridin-3-yl)amine (15 g) and N-vinyl-carbamic acid benzyl ester (9.4 g) are dissolved in toluene (200 ml), then thereto is added p-toluenesulfonic acid monohydrate(100 mg), and the mixture is stirred at 80° C. for 4 hours under nitrogen flow. After allowing to cooled to room temperature, the reaction solution is added to a mixture of a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with a saturated brine...

example 2

(1) (S)-1-Phenylethylalchol (16.1 g) and pyridine (10.7 ml) are dissolved in chloroform (100 ml), and thereto is added a solution (100 ml) of p-nitrophenyl chloroformate (26.6 g) in chloroform. The reaction solution is stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=85:15→70:30) to give p-nitrophenyl (S)-1-phenylethyl carbonate (35.6 g).

(2) (2 R,4S-)-4-Amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (34.3 g), p-nitrophenyl (S)-1-phenylethyl carbonate (35.3 g) and triethylamine (17.1 ml) are dissolved in acetonitrile (250 ml) and the mixture is heated under reflux for 3 hours. The reaction solution is partitioned by adding ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated ...

example 3

(1) (2S,4R)-(2-Ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)carbamic acid (S)-1-phenylethyl ester (840 mg) and pyridine (0.956 ml) are dissolved in methylene chloride (5 ml). After adding dropwise a solution (5 ml) of ethyl chloroformate (1.13 ml) in methylene chloride under ice-cooling, the mixture is stirred at room temperature for one hour. The reaction solution is washed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=90:10→60:40) to give (2S,4R)-2-ethyl-6-methoxy-4-[(S)-1-phenylethoxycarbonylamino]-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1.00 g). MS (m / z): 428 [M+H]+

(2) Ten % palladium / carbon (100 mg) is added to a solution (10 ml) of (2S,4R)-2-ethyl-6-methoxy-4-[(S)-1-phenylethoxycarbonylamino]-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxyl...

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Abstract

A novel compound of the formula (I): wherein R1 is alkoxycarbonyl or the like, R2 is alkyl or the like; R3 is hydrogen or the like; R4 is alkylene or the like; R5 is optionally substituted heterocyclic group; R6, R7, and R8 are independently hydrogen; alky, alkoxy, or the like; R10 is optionally substituted aromatic ring, or the like; or a pharmaceutically acceptable salt thereof, which has an inhibitory activity against cholesteryl ester transfer protein (CETP).

Description

TECHNICAL FIELD The present invention relates to a novel tetrahydronaphthyridine derivative having an inhibitory activity against cholesteryl ester transfer protein (CETP). BACKGROUND ART Hypercholesterolemia, especially high serum level of low-density lipoprotein (LDL) cholesterol, has been revealed to be a risk factor of arteriosclerotic diseases by a number of epidemiological surveys. Actually, drugs capable of decreasing LDL cholesterol level such as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors have been used with the aim of preventing coronary artery diseases, and demonstrated to have some benefits in many large scale clinical tests. However, their preventive effect on coronary diseases is limited to some extent, and is not satisfactory enough yet. Recently, low serum level of high density lipoprotein (HDL) cholesterol has been revealed to be a potent risk factor of arteriosclerotic diseases by a number of epidemiological surveys and large scale clinical tes...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61K31/4745C07D471/02C07D471/00C07D471/04
CPCC07D471/04A61P3/00A61P3/04A61P3/06A61P7/02A61P9/00A61P9/10A61P9/12A61P3/10
Inventor KUBOTA, HITOSHINAKAMURA, YOSHINORIHIGASHIJIMA, TAKANORIYAMAMOTO, YASUOOKA, KOZOIGARASHI, SHIGEKI
Owner MITSUBISHI TANABE PHARMA CORP
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